Activation of Downstream Signals by the Long Form of the Leptin Receptor
Open accessAbstract
The adipocyte-derived hormone leptin signals the status of body energy stores by activating the long form of the leptin receptor (LRb). Activation of LRb results in the activation of the associated Jak2 tyrosine kinase and the transmission of downstream phosphotyrosine-dependent signals. We have investigated the signaling function of mutant LRb intracellular domains under the control of the extracellular erythropoietin (Epo) receptor. By using this system, we confirm that two tyrosine residues in the intracellular domain of murine LRb become phosphorylated to mediate LRb signaling; Tyr(985) controls the tyrosine phosphorylation of SHP-2, and Tyr(1138) controls STAT3 activation. We furthermore investigated the mechanisms by which LRb controls downstream ERK activation and c-fos and SOCS3 message accumulation. Tyr(985)-mediated recruitment of SHP-2 does not alter tyrosine phosphorylation of Jak2 or STAT3 but results in GRB-2 binding to tyrosine-phosphorylated SHP-2 and is required for the majority of ERK activation during LRb signaling. Tyr(985) and ERK activation similarly mediate c-fos mRNA accumulation. In contrast, SOCS3 mRNA accumulation requires Tyr(1138)-mediated STAT3 activation. Thus, the two LRb tyrosine residues that are phosphorylated during receptor activation mediate distinct signaling pathways as follows: SHP-2 binding to Tyr(985) positively regulates the ERK --> c-fos pathway, and STAT3 binding to Tyr(1138) mediates the inhibitory SOCS3 pathway.
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Phosphorylation of Tyr1138 recruits STAT3, which is phosphorylated by Jak2, dimerizes, translocates to the nucleus, and functions as a transcription factor.
“phosphorylation of Tyr1138 recruits signal transduction and activator of transcription-3 (STAT3), which is then itself phosphorylated on tyrosine residues by Jak2 allowing it to dimerize and translocate to the nucleus where it functions as a transcription factor (6, 23, 186).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [6]
Phosphorylation of Tyr985 recruits SHP-2 to LepRb, leading to ERK pathway activation in cultured cells and recruitment of SOCS-3.
“Phosphorylation of Tyr985 recruits SH2-domain-containing phosphatase-2 (SHP-2) to LepRb, leading to the activation of the extracellular signal regulated (ERK) signaling pathway in cultured cells, as well as the recruitment of suppressor of cytokine signaling-3 (SOCS-3), a negative regulator of LepRb signaling (6, 21, 22).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [6]
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“Phosphorylation of Tyr985 recruits SH2 domain-containing phosphatase-2 (SHP-2) to LepRb, leading to the activation of the extracellular signal regulated (ERK) signaling pathway in cultured cells, as well as the recruitment of suppressor of cytokine signaling-3 (SOCS-3), a negative regulator of LepRb signaling (6, 21,…”
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Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function
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Activation of Stat3 Signaling in AgRP Neurons Promotes Locomotor Activity
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LRb signals act within a distributed network of leptin‐responsive neurones to mediate leptin action
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Leptin, neuroinflammation and obesity
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Li, M., Li, Z., Morris, D. L., & Rui, L. (2007) · Endocrinology · doi:10.1210/en.2006-1010 · Cited by 39 · see citing works
Boelen, A., van Beeren, M., Vos, X., Surovtseva, O., Belegri, E., Saaltink, D.-J., Vreugdenhil, E., Kalsbeek, A., Kwakkel, J., & Fliers, E. (2012) · Thyroid · doi:10.1089/thy.2011.0289 · Cited by 35 · see citing works
Robertson, S., Ishida-Takahashi, R., Tawara, I., Hu, J., Patterson, C. M., Jones, J. C., Kulkarni, R. N., & Myers, M. G. (2010) · Diabetes · doi:10.2337/db09-1556 · Cited by 30 · see citing works
Self-citation
- Authors
- Banks, A. S., Davis, S. M., Bates, S. H., & Myers, M. G.
- Affiliations
- Joslin Diabetes Center (US)
- Corresponding author
- Myers, Martin G.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-05
- Volume
- 275
- Issue
- 19
- Pages
- 14563-14572
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2062570379
- Cited by
- 797
- References
- 65
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 18 · 2023: 5 · 2022: 20 · 2021: 26 · 2020: 33 · 2019: 28 · 2018: 29 · 2017: 33 · 2016: 18 · 2015: 45 · 2014: 58 · 2013: 57 · 2012: 36
- FWCI
- 9.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK56731)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- leptin receptor, JAK2 tyrosine kinase, SHP2, STAT3, ERK activation, c-fos, SOCS3, tyrosine phosphorylation, Grb2, erythropoietin receptor, signal transduction, adipokine signaling
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Carrier Proteins, Cell Line, Enzyme Activation, Humans, Mutation, Phosphorylation, Proteins, Receptors, Cell Surface, Repressor Proteins, Transcription Factors, Tyrosine, Signal Transduction, Genes, fos, Protein Tyrosine Phosphatases, Mitogen-Activated Protein Kinases, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Suppressor of Cytokine Signaling Proteins, GRB2 Adaptor Protein, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Receptors, Leptin, Protein Tyrosine Phosphatase, Non-Receptor Type 11
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